title: Structural feature study of benzofuran derivatives as farnesyltransferase inhibitors.
abstract: Ras proteins are small GTPases (G-proteins) that play a key role in cell growth and cell proliferation in the mitogen-activated protein kinase signal transduction pathway. Farnesylation is a critical step for membrane binding and the biological function of G-proteins. In the present investigation, we have studied the structural features of some molecules that are acting on the farnesyltransferase (FTase) enzyme for the inhibition of the farnesylation step in G-proteins. The benzofuran derivatives have activity against FTase inhibition and antiproliferative activity on QG56 cell lines. The result obtained from the quantitative structure-activity relationship study of these compounds shows that the models have significant predictive power and stability, as shown by statistical parameters such as R(2), Q(2), R(2)(pred), R(2)(m), F-value, Durbin-Watson, variable inflation factor values, Mahalanobis, and Cook's distances. The contribution of each descriptor for the activities (β-coefficients) reveals that the P-VSA descriptors (van der Waals surface area descriptors) such as vsa_pol, vsa_acc and SMR_VSA3 are the major contributors for the activity, along with other descriptors such as the partition coefficient, the partial charge, the atom and bond count and the adjacency, and distance descriptors. Earlier study on the FTase enzyme in our laboratory reveals that the existence of positively-charged groups on the FTase active site is important for drug design. It is also showing that the presence of hydrogen bonding donor and acceptor groups, together with negatively charged substituents is critical for improved activity by this series of molecules. These results offer important clues for the development of novel FTase inhibitors.
authors.affiliation: REQUIMTE, Departamento de Química, Faculdade de Ciências, Universidade do Porto, Porto, Portugal. hari.moorthy@fc.up.pt
authors.forename: N S Hari Narayana
authors.initials: NS
authors.lastname: Moorthy
authors.forename: Sergio F
authors.initials: SF
authors.lastname: Sousa
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Ramos
authors.forename: Pedro A
authors.initials: PA
authors.lastname: Fernandes
mesh_terms: D001572:Benzofurans / Q000737:chemistry / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D021281:Quantitative Structure-Activity Relationship
chemical_list: D001572:Benzofurans; D004791:Enzyme Inhibitors; D051231:Farnesyltranstransferase; C105430:benzofuran